The overall goal of this project is to improve the proton therapy dose distributions that can confidently be delivered. The improvements are expected to be threefold: (1) the use with confidence of tighter margins around the target volume, thus reducing normal tissue complications, (2) reduced uncertainty in treatment planning and delivery through techniques such as image-guided interventions and robust optimization, and (3) confidence that the dose distribution which is delivered agrees, within explicit bounds, with what was planned. While proton therapy has been practiced for several decades with success, there remain a number of uncertainties and limitations that can compromise the benefit of protons, either by requiring undesirably large margins around the clinical target volume (with concomitant over irradiation of normal tissues) or by preventing the use of protons or limiting their optimal application in some important sites (e.g., lung). The hypothesis of this project is that improved accuracy in treatment planning and delivery methods and the application of intensity-modulated proton therapy (IMPT) and optimization techniques will lead to reductions in margins and in the difference between planned and delivered dose distributions; also that these reductions will be by a factor of at least 2 compared with the current values. To test this hypothesis, we will (1) quantify the impact of current uncertainties and the gains made possible with strategies to reduce uncertainties, (2) evaluate the potential of IMPT and optimization techniques for reducing margins and mitigating the impact of uncertainties, and (3) quantify the confidence limits on the planned dose distributions and verify that the differences between planned and delivered dose distributions are within confidence limits. The significance of the proposed research is that it should lead to reductions in margins, greater sparing of normal tissues, and greater potential for dose intensification. Additionally, it should lead to greater confidence that the planned and delivered proton therapy dose distributions are very nearly the same. The significance is further heightened by the need to minimize the possibility of suboptimal application of this very powerful modality whose use is rapidly proliferating around the world.